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Systemic Therapy for Older Women With Breast Cancer

Systemic Therapy for Older Women With Breast Cancer

ABSTRACT: Breast cancer is a common problem in older women. As the number of medical illnesses increases with age and the life expectancy decreases, the benefits of systemic therapy for women with breast cancer become questionable. All women over age 65 years are at high enough risk of breast cancer to consider the risk/benefit ratio of preventive therapy with tamoxifen (Nolvadex) or participation in the Study of Tamoxifen and Raloxifene (STAR) trial. Adjuvant chemotherapy and hormonal therapies for early breast cancer significantly improve disease-free and overall survival; recommendations for their use are based on risk of tumor recurrence. Use of tamoxifen in the adjuvant setting in women with receptor-positive tumors is a relatively simple decision in light of its favorable toxicity profile. The delivery of adjuvant chemotherapy is a more complicated decision, and the patient’s wishes, estimated life expectancy, presence of comorbid conditions, and estimated benefit from treatment should be considered. The primary goal of the treatment of metastatic breast cancer is palliation. We discuss trials specific to older women and make appropriate treatment recommendations. Unfortunately, there is a paucity of data from clinical trials in women over age 70 years. However, because the clinical trial is the primary scientific mechanism for testing the efficacy of a treatment, every effort should be made to enter older women into treatment protocols. [ONCOLOGY 15(3):280-299, 2001]

Introduction

Cancer is a common and more
frequent problem in older persons.[1,2] Currently, about 50% of breast cancer cases occur in women aged 65
years and older. Illnesses that were disabling and often fatal in the past are
now treated effectively, and people are living longer. Treatments for cancer are
also evolving, and prolonging the lives of cancer patients is now possible for
many malignancies, including breast cancer.

The incidence of breast cancer in the United States has begun to
decrease.[3] Mortality rates have also been decreasing in recent years,[4] and
with increased use of mammographic screening, breast cancers are being detected
at earlier, more curable stages. Moreover, adjuvant therapies have become more
successful, and new drugs (such as the taxanes) have improved response rates and
tolerability of therapy for patients with metastatic disease.

Regardless of age, the treatment of breast cancer involves
complex decisions about risks vs benefits for each patient. As age increases,
the number of comorbidities increases,[2] making the potential risks of systemic
therapy greater and the potential benefits smaller. Preventing breast cancer and
its recurrence and/or progression, however, becomes more important as we are
able to help people with many diseases live longer.

This article will discuss the use of hormonal therapy and
chemotherapy in older women. There is no unanimously accepted definition of
"older," but most clinicians consider patients aged 65 years and over
to be in this category.

Decreasing the Incidence
of Breast Cancer

The incidence of breast cancer increases with age.[5] Potential
strategies to decrease the risk of breast cancer in the geriatric population
include changes in life-style such as increasing exercise, dietary modifications
such as following a low-fat diet, and drug therapy with selective
estrogen-receptor modulators. The data suggesting that life-style and dietary
changes may lower breast cancer risk are controversial and far from compelling.
Since most women with breast cancer are likely to die of other causes, exercise
and dietary modification are prudent recommendations for most patients,
irrespective of breast cancer risk.

At present, the use of selective estrogen-receptor modulators is
the most exciting option for breast cancer prevention. These agents include
tamoxifen (Nolvadex), raloxifene (Evista), and toremifene (Fareston).[6] Only
tamoxifen has been approved by the Food and Drug Administration (FDA) to
decrease the incidence of breast cancer. Raloxifene has been approved for the
treatment of osteoporosis, and preliminary data suggest that it may also
significantly decrease the incidence of breast cancer.[7,8]

Trials of Tamoxifen

Three published trials have evaluated the potential preventive
benefit of tamoxifen: the National Surgical Adjuvant Breast and Bowel Project
Prevention trial (NSABP P-1),[9] the Royal Marsden Hospital chemoprevention
trial,[10] and an Italian randomized trial in women who had undergone a
hysterectomy (Table 1).[11] The major differences between these trials have been
discussed in detail elsewhere.[12] The NSABP P-1 trial was the only one of the
three with a large cohort of older women. It showed a 50% reduction in the
incidence of invasive and noninvasive breast cancer among women who took
tamoxifen.

NSABP P-1 Trial: In NSABP P-1, 30% of participants were 60
years of age and older and 6% were over the age of 70 years.[9] Women with a
1.67% risk of developing breast cancer within 5 years were eligible for the
trial. All women aged 60 years or older in the United States meet these
criteria, irrespective of other risk factors. Tamoxifen lowered the incidence of
both in situ and invasive lesions. There was a 55% reduction in the incidence of
invasive breast cancer associated with tamoxifen use in older women; the 5-year
probability of invasive breast cancer developing in women 60 years of age and
older decreased from almost 4% to about 2%.

This effect was limited to estrogen-receptor (ER)-positive
invasive tumors; ER-negative tumors were found with similar frequency in the
tamoxifen and placebo-treated groups. Risks associated with the use of tamoxifen
in older women included a significantly higher incidence of endometrial cancer
and thromboembolic events. In addition, tamoxifen use increased the frequency of
vasomotor and gynecologic symptoms and problems with sexual function.[13]

Royal Marsden Hospital Trial: The Royal Marsden Hospital
chemoprevention trial included women at increased risk of breast cancer based on
family history.[10] As such, the majority of women in this trial (61%) were
younger than age 50 years; women over age 70 years were ineligible. At a median
follow-up of 70 months, the use of tamoxifen did not decrease the incidence of
breast cancer.

Italian Trial: The Italian randomized trial included any
woman who had undergone a hysterectomy.[11] Approximately one-third of women in
the Italian trial were over age 55 years, and only 11.7% were age 60 or older;
women over age 70 were ineligible. No decrease in the incidence of breast cancer
was associated with the use of tamoxifen, but women in this trial were at lower
risk for breast cancer compared to women in the other two reported trials.

Both the Royal Marsden Hospital chemoprevention trial and the
Italian randomized trial allowed women who were taking hormone replacement
therapy to participate. In the Italian trial, the rate of breast cancer was
lower among women taking hormone replacement therapy plus tamoxifen than in the
cohort taking replacement therapy alone (log rank P = .0216). This is not
currently accepted practice in the United States.

Trials of Raloxifene

Raloxifene is another selective estrogen-receptor modulator with
a toxicity profile similar to tamoxifen that allegedly causes fewer endometrial
changes.[14] In the Multiple Outcomes of Raloxifene (MORE) trial, 7,705 women
with osteoporosis were randomly assigned to receive one of two different doses
of raloxifene or placebo for 3 years.[8] Participants were primarily white (95%)
and over age 62 years (82%). At 40 months of follow-up, women taking raloxifene
had 43% fewer vertebral fractures and a 76% lower incidence of invasive breast
cancer.

The rate of breast cancer for all arms of this trial was low
(10.5 per 1,000 women given placebo and 2.5 per 1,000 women given raloxifene),
but the difference was still statistically significant (response rate [RR] =
0.24; 95% confidence interval [CI] = 0.13-0.44). Hormone-receptor-positive
tumors were preferentially prevented, and thrombotic events were more prevalent
in women receiving raloxifene in this trial as well, but no increase in
endometrial cancer was seen.

A second prevention trial (NSABP P-2) comparing tamoxifen with
raloxifene, the STAR trial, is underway. Targeted accrual is approximately
22,000 postmenopausal women.

Calculating Breast Cancer Risk

All women over age 60 years were eligible for NSABP P-1 based on
their calculated risk of breast cancer. Breast cancer risk assessment is
becoming a routine part of general medical care, and many women are reviewing
the risks and benefits of "preventive" tamoxifen with their doctors.
The risk of developing breast cancer can be easily calculated using the Gail
model. An updated version of this risk assessment tool is available on the
Internet at http://cancertrials.nci.nih.gov.

Moreover, Gail and his colleagues have recently provided
detailed clinical data on how to calculate the potential benefits and risks of
tamoxifen therapy, factoring in available epidemiologic data on the risks of
thromboembolic complications and endometrial cancer (Table 2).[15] For example,
in a 65-year-old white woman with an intact uterus and a thromboembolic risk
similar to that of patients in the NSABP P-1 trial, the 5-year risk of invasive
breast cancer needs to exceed 7.0% in order for the benefits of tamoxifen
therapy to outweigh the risks. The benefits of tamoxifen would outweigh the
risks in the same woman who had a hysterectomy and whose risk was 3.5%.

In older women, the preventive benefits of tamoxifen may
outweigh the risks, but these women should be counseled about the risks and
benefits of preventive tamoxifen. They should also be encouraged to participate
in the STAR trial.

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